Effects of methylprednisolone and MK-801 on functional recovery after experimental chronic spinal cord injury (original) (raw)
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A STUDY OF METHYLPREDNISOLONE NEUROPROTECTION AGAINST ACUTE INJURY TO THE RAT SPINAL CORD IN VITRO
Methylprednisolone sodium succinate (MPSS) has been proposed as a first-line treatment for acute spinal cord injury (SCI). Its clinical use remains, however, controversial because of the modest benefits and numerous side-effects. We investigated if MPSS could protect spinal neurons and glia using an in vitro model of the rat spinal cord that enables recording reflexes, fictive locomotion and morphological analysis of damage. With this model, a differential lesion affecting mainly either neurons or glia can be produced via kainate-evoked excitotoxicity or application of a pathological medium (lacking O 2 and glucose), respectively. MPSS (6-10 lM) applied for 24 h after 1-h pathological medium protected astrocytes and oligodendrocytes especially in the ventrolateral white matter. This effect was accompanied by the return of slow, alternating oscillations (elicited by NMDA and 5-hydroxytryptamine (5-HT)) reminiscent of a sluggish fictive locomotor pattern. MPSS was, however, unable to reverse even a moderate neuronal loss and the concomitant suppression of fictive locomotion evoked by kainate (0.1 mM; 1 h). These results suggest that MPSS could, at least in part, contrast damage to spinal glia induced by a dysmetabolic state (associated to oxygen and glucose deprivation) and facilitate reactivation of spinal networks. Conversely, when even a minority of neurons was damaged by excitotoxicity, MPSS did not protect them nor did it restore network function in the current experimental model. Ó
Experimental Neurology, 2009
Currently, methylprednisolone sodium succinate (MPSS) is the standard treatment following acute spinal cord injury (SCI) as a consequence of the results obtained from the National Acute Spinal Cord Injury Studies. However, many have questioned the efficacy of MPSS because of its marginal effects. Additionally there has been criticism of both study design and statistical interpretation. The functional consequences of experimental SCI have been assessed in many ways. The purpose of this investigation was to determine the effects of MPSS vs. saline solution (SS) following moderate T10 contusion injury in rat. Functional recovery was evaluated using the 21-point Basso, Beattie and Bresnahan (BBB) locomotor recovery scale, the inclined plane, the beam walk, footprint analysis and the horizontal ladder. To optimize the precision and accuracy of functional results we examined the locomotion on a treadmill using three-dimensional (3D) analysis. Stereology was used to estimate the amount of damaged tissue. The results of the traditional functional methods showed that administration of the NASCIS dosage of MPSS following acute spinal cord contusion did not lead to any significant differences in the functional recovery of MPSS-vs. SS-treated animals. More importantly, the results of the 3D kinematic showed that the MPSS administration did not affect the flexion/extension of the hip, knee and ankle joints during the step cycle. Finally, stereological results revealed no statistically significant differences between the two experimental groups. Altogether, our results support data previously reported by several authors, suggesting that MPSS does not lead to improved functional outcome following experimental acute SCI.
Brain Research, 2000
Ž. To date, relatively little progress has been made in the treatment of spinal cord injury SCI-related neurological impairments. Until Ž. now, methylprednisolone MP is the only agent with clinically proven beneficial effect on functional outcome after SCI. Although the mechanism of action is not completely clear, experimental data point to protection against membrane peroxidation and edema reduction. The melanocortin melanotropin is known to improve axonal regeneration following sciatic nerve injury, and to stimulate corticospinal outgrowth after partial spinal cord transection. Recently, we showed that intrathecally administered a MSH had beneficial effects on Ž. functional recovery after experimental SCI. Since both drugs have shown their value in intervention studies after experimental spinal Ž. cord injury ESCI , we decided to study the effects of combined treatment. Our results again showed that a MSH enhances functional recovery after ESCI in the rat and that MP, although not affecting functional recovery adversely by itself, abolished the effects observed with a MSH when combined. Our data, thus, suggest that the mechanism of action of MP interferes with that of a MSH.
Journal of Korean Neurosurgical Society, 2016
The aim of our study was to evaluate the neuroprotective functions of the combination therapy using methylprednisolone (MP) and tranilast (TR) after spinal cord injury (SCI) in adult rats. Methods : Spinal cord compression injury model was achieved using Yasargil aneurysm clip. Rats were divided into control group, MP group, TR group, and combination therapy group using TR and MP. Rat models were assessed for locomotor functional recovery using Basso, Beattie, and Bresnahan (BBB) score, spinal cord water content and myeloperoxidase (MPO) activity 24 hours post SCI, haematoxylin and eosin staining and glial fibrillary acid protein (GFAP) staining at 7 and 14 days post SCI. Results : The spinal cord water content and MPO activity in the combination therapy group was significantly lower than the control group and the individual therapy groups p<0.05. The combination therapy group had significantly higher BBB scores than control group and individual therapy groups (p<0.05). At one week after SCI, GFAP expression in the combination group was significantly lower than the control group (p<0.05) but there was no significant difference compared to the individual therapy groups (p>0.05). At 2 weeks after SCI there was a slight decrease in GFAP expression compared to the first week but the difference was not statistically significant (p>0.05), GFAP expression between the groups was not statistically significant p>0.05. Conclusion : Combining MP and TR is therapeutically more effective in improving functional recovery, inhibiting inflammation and glial scar formation after acute SCI.
Revista Brasileira De Ortopedia, 2015
The aim here was to conduct a review of the literature on pharmacological therapies for modifying the neurological status of patients with spinal cord injuries. The PubMed database was searched for articles with the terms "spinal cord injury AND methylprednisolone/GM1/apoptosis inhibitor/calpain inhibitor/naloxone/tempol/tirilazad", in Portuguese or in English, published over the last five years. Older studies were included because of their historical importance. The pharmacological groups were divided according to their capacity to interfere with the physiopathological mechanisms of secondary injuries. Use of methylprednisolone needs to be carefully weighed up: other anti-inflammatory agents have shown benefits in humans or in animals. GM1 does not seem to have greater efficacy than methylprednisolone, but longer-term studies are needed. Many inhibitors of apoptosis have shown benefits in in vitro studies or in animals. Naloxone has not shown benefits. Tempol inhibits the main consequences of oxidation at the level of the spinal cord and other antioxidant drugs seem to have an effect superior to that of methylprednisolone. There is an urgent need to find new treatments that improve the neurological status of patients with spinal cord injuries. The benefits from treatment with methylprednisolone have been questioned, with concerns regarding its safety. Other drugs have been studied, and some of these may provide promising alternatives. Additional studies are needed in order to reach conclusions regarding the benefits of these agents in clinical practice.
Turkish Neurosurgery, 2015
AIm: To evaluate the neuroprotective effects of adalimumab in an experimental spinal cord injury model and compare them with those of the widely-used methylprednisolone. mATERIAl and mEThODS: Forty male Wistar rats were divided into 5 as the sham, trauma, adalimumab, methylprednisolone, and adalimumab+methylprednisolone groups. Only laminectomy was performed in the sham group. Laminectomy and trauma was performed to the trauma group but no treatment was given. A single dose of 40 mg/kg subcutaneous adalimumab was administered after the laminectomy and trauma to group 3. A single dose of intravenous 30 mg/kg methylprednisolone was administered right after laminectomy and trauma to group 4. Single doses of 40 mg/kg adalimumab and 30 mg/kg methylprednisolone were administered together after laminectomy and trauma to group 5. Serum malondialdehyde (MDA), TNF-α, IL-1β and IL-6 levels were measured and sections were obtained for histopathological study at the end of the 7 th day. RESulTS: MDA, TNF-α, IL-1β and IL-6 levels in serum were significantly decreased in the adalimumab group with clinical and histopathological improvement not less than the methylprednisolone group. The serum MDA levels were similar when the two drugs were given together or separately but there was a statistically quite significant decrease in TNF-α, IL-1β and IL-6 levels with concurrent use. Statistically significantly better results were obtained on histopathological evaluation with the use of both drugs together. COnCluSIOn: This study revealed that adalimumab is as effective as methylprednisolone in compressive spinal cord injury in rats.
Long-term effects of methylprednisolone following transection of adult rat spinal cord
European Journal of Neuroscience, 1999
Clinically, high-dose treatment with the glucocorticosteroid, methylprednisolone (MP), within 8 h after spinal cord injury, has been shown to improve neurological recovery. The current standard of care is to administer MP as a bolus of 30 mg/kg followed by a 23-h infusion of 5.4 mg/kg/h to spinal cord injured patients. To better understand the role of MP in neuroprotection, we have studied how MP administration affects macrophage accumulation, tissue loss, and axonal dieback at 1, 2, 4 and 8 weeks after a complete transection of the eighth thoracic spinal cord in the adult rat. A 30 mg/kg dose of MP was administered intravenously at 5 min, and 2 and 4 h after injury. The number of ED1 (antibody against microglia/macrophages) -positive cells was quanti®ed in a 500-mm-wide strip of tissue directly adjacent and parallel to the transection. At all time points, MP treatment led to a signi®cant decrease in the number of ED1-positive cells in both rostral and caudal stumps. Over the 2-month post-transection period, the average MP-induced reduction in the number of ED1-positive cells was 82% in the rostral cord stump and 66% in the caudal stump. Using a computerized image analysis system, it was observed that MP treatment resulted in a signi®cant reduction in tissue loss in both cord stumps at 2, 4 and 8 week post-injury. Over the 2-month post-lesion period, the average MP-induced reduction in tissue loss in the caudal cord stump was higher than that in the rostral stump; 48 versus 37%, respectively. Immunostaining for neuro®laments and growthassociated protein-43 (GAP-43) revealed the presence of numerous axons near and in the lesion site. Anterograde neuronal tracing with biotinylated dextran amine showed that, in MP-treated animals, dieback of vestibulospinal ®bres, but not of corticospinal ®bres, was signi®cantly diminished at all time points studied. In addition, with MP administration, 1 and 2 weeks after injury, an increase in the number of vestibulospinal ®bres was found at 1 and 2 mm from the transection, suggesting transient regenerative sprouting of these ®bres. The results demonstrate that treatment with MP shortly after spinal cord transection in the adult rat led to a long-term reduction of ED1-positive cells and spinal tissue loss, reduced dieback of vestibulospinal ®bres, and a transient sprouting of vestibulospinal ®bres near the lesion at 1 and 2 weeks post-lesion. The possible relationships between the in¯ammatory changes, spinal tissue sparing, and axonal survival and sprouting are complex and need to be further explored.
Spinal Cord, 1998
The demyelination process is an important factor contributing to long term sensory and motor impairments after spinal cord injury (SCI). Exposure of axonal K + channels after demyelination may contribute to blockage of action potentials across the injury site. A K + channel blocker, 4-aminopyridine (4-AP), has been eective in restoring some sensory and motor impairment in incomplete SCI patients. The long-term eect of this compound in chronic model of SCI is not known. In this study, after a compression injury of 50 grams in rats, a randomized treatment was initiated 3 weeks after the initial injury which was followed by daily administration of 4-AP at 2 mg/kg (n=8), 4 mg/kg (n=8), and 6 mg/kg (n=8) for 4 weeks. A group of methylprednisolone (MP)-treated (30 mg/kg, n=8) and non-treated animals (n=8) were included for comparison. The functional motor outcome was measured in each animal at regular time points up to 4 weeks post-treatment. All animals receiving 6 mg/ kg developed generalized seizure and were excluded from the study. In the other animal groups, analysis of the behavioral outcome and neuro-pathological changes were essentially similar and did not show any signi®cant eect of treatment. Our data indicate that daily administration of 4-AP, over 4 weeks of treatment period, lacks any signi®cant eect on axonal function in chronically injured rats. This could be due to (a) lack of signi®cant numbers of demyelinated axons which could improve the functional outcome and (b) a treatment regimen that was not adequate to contribute to a better functional outcome. One time bolus-administration of MP at 30 mg/kg also did not ensure a better functional outcome.
Spinal Cord, 1999
Objectives: To determine whether MK801, an NMDA receptor antagonist, blocks glutamate excitotoxicity directly or via other mechanisms such as improving blood supply at the injury site in a rat model of spinal cord injury (SCI). In the present study, the eects of pre-and posttreatment with MK801 on axonal function, spinal cord blood¯ow (SCBF) and cord water content were studied after acute SCI in rats. Methods: Somatosensory evoked potentials (SSEPs) and cerebellar evoked potentials (CEPs) were used to quantify electrophysiological function, and the hydrogen clearance technique and wet-dry weight measurements were used to measure SCBF and cord water content, respectively. Twenty rats received a 21 g clip compression injury of the cord at T1, and were then randomly and blindly allocated to either MK801 or saline groups. Each rat received an intravenous infusion of drug or saline four times during the experiment (16 min/infusion) with the ®rst infusion (MK801 3 mg/kg) beginning 8 min pre-injury, and the other infusions (MK801 1.5 mg/kg) at 1 h intervals after injury. Control experiments on uninjured rats were performed in 10 rats using the same procedure as above except the clip compression injury of the cord was omitted. Results: In the MK801 groups with or without SCI, the amplitude of the evoked potential peaks, especially the SSEPs, was signi®cantly lower than in the saline group. There were no dierences in SCBF or cord water content between the MK801 and saline groups. Conclusion: Pre-and posttreatment with MK801 inhibits evoked potentials, but does not improve SCBF or cord edema after acute compression SCI in rats. For the ®rst time it has been shown that MK801 produced a blockade of glutamate excitatory transmission in aerent pathways after SCI. Further work is required to determine whether this inhibition is reversible and related to neuroprotection and functional recovery after SCI.
Cell J, Vol 23, No 6, November 2021, 94
Objective: In spinal cord injury (SCI), the primary mechanical damage leads to a neuroinflammatory response and the secondary neuronal injury occurs in response to the release of reactive oxygen species (ROS). In addition to the suppression of inflammation, autophagy plays a significant role in the survival of neurons during secondary SCI. The present study aimed to examine the anti-inflammatory and autophagic effects of agmatine and rapamycin in SCI and to compare the results with methylprednisolone (MP) used in the clinic. Materials and Methods: In this animal-based experimental study, thirty adult male Sprague-Dawley rats were randomly divided into five groups as sham-control, injury, injury+MP, injury+rapamycin, injury+agmatine groups. SCI was induced by compressing the T7-8-9 segments of the spinal cord, using an aneurysm clip for one minute, and then rats were treated daily for 7 days. Seven days post-treatment, damaged spinal cord tissues of sacrificed rats were collected for microscopic and biochemical examinations using histopathologic and transmission electron microscope (TEM) scores. Malondialdehyde (MDA) and glutathione peroxidase (GPx) levels were spectrophotometrically measured. Results: The results of this study showed that the damaged area was smaller in the rapamycin group when compared to the MP group. Many autophagic vacuoles and macrophages were observed in the rapamycin group. Degeneration of axon, myelin, and wide edema was observed in SCI by electron microscopic observations. Fragmented myelin lamellae and contracted axons were also noted. While MDA and GPx levels were increased in the injury group, MDA levels were significantly decreased in the agmatine and MP groups, and GPx levels were decreased in the rapamycin group. Conclusion: The results of our study confirmed that rapamycin and agmatine can be an effective treatment for secondary injury of SCI.